Associations of SGLT-2i with Cardiorenal Outcomes Among Diabetics with Prostate Cancer on Hormone Therapy

Background Studies have reported associations between prostate cancer, type II diabetes mellitus (T2DM) and cardiovascular disease in the context of treatment with hormone therapy (HT). This study aimed to assess the role of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) in preventing adverse cardiovascular and renal outcomes in diabetics with prostate cancer. Methods Patients ≥ 18 years of age with T2DM and prostate cancer who received HT between August 1, 2013, and August 31, 2021, were identified using the TriNetX research network. Patients were divided into two cohorts based on treatment with SGLT2i or alternative antidiabetic therapies. The primary outcome was the composite of all-cause mortality, new onset heart failure (HF), acute myocardial infarction (MI), and peripheral artery disease over two years from HT initiation. Results After propensity score matching, 2,155 patients remained in each cohort. The primary composite outcome occurred in 218 patients (16.1%) in the SGLT2i cohort versus 355 patients (26.3%) in the non-SGLT2i cohort (HR 0.689, 95% CI 0.582–0.816; p < 0.001). Furthermore, SGLT2i were associated with significantly lower odds of HF, HF exacerbation, peripheral artery disease, atrial fibrillation/flutter, cardiac arrest, need for renal replacement therapy, overall emergency room visits/hospitalizations and all-cause mortality. Conclusions Use of SGLT2i for the treatment of T2DM among patients with prostate cancer on HT is associated with favorable cardiovascular, renal and all-cause mortality outcomes. This observation supports the hypothesis that a therapeutically relevant link exists between HT and cardiovascular disease in the context of prostate cancer.


Introduction
Prostate cancer is the most common type of cancer among men, aside from skin cancer, with an estimated number of new cases in the US exceeding 288,000 in 2023 1 .Many patients with prostate cancer live beyond a decade from diagnosis and frequently die from non-prostate cancer related causes 1,2 .Cardiovascular risk factors, including type 2 diabetes mellitus (T2DM) and cardiovascular disease are prevalent among patients with prostate cancer and represent a leading cause of mortality in this patient population [2][3][4] .Hormone therapy (HT), which is the backbone of prostate cancer therapy, has also been associated with cardiotoxicity through alterations in body composition, lipid abnormalities and impaired glucose control 5 .Even though the association of prostate cancer and HT with development of T2DM and cardiovascular disease is known for decades, a recent study reported that a signi cant portion of prostate cancer patients have undiagnosed or poorly controlled T2DM 6,7 .This suggests that there is an unmet need for early diagnosis and appropriate treatment of T2DM tailored towards the prevention of cardiovascular disease.
Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) have been associated with signi cant cardiovascular and renal bene ts including prevention of heart failure (HF), renal failure and cardiovascular mortality, and have been recommended for the treatment of patients with T2DM at risk for or with established cardiovascular disease 8 .Despite the signi cant potential bene ts of SGLT2i in patients with prostate cancer, patients with active cancer were excluded from the clinical trials that established the cardiorenal bene ts of SGLT2i [9][10][11][12] .Therefore, their exact role and size of impact among patients with T2DM and prostate cancer treated with HT has not been established yet.We believe that improved understanding of the interaction of HT and SGLT2i in patients with prostate cancer will lead to a biologically sound strategy to mitigate the risk of cardiovascular disease.The aim of this study was to assess the incidence of adverse cardiovascular and renal outcomes in patients with prostate cancer on HT and T2DM treated with versus without SGLT2i using a large real-world database.

Study Oversight
Each of the authors contributed to various aspects of the study, including data analysis, manuscript development as well as review.The need for Institutional Review Board (IRB) approval was waived by Lahey Clinic IRB due to the use of deidenti ed data for the analysis.The study ndings are reported per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies.

Data Source and Study Setting
This study utilized the TriNetX Analytics Network -Research Network, which is a collaborative health research network that draws upon de-identi ed electronic health records (EHRs) data from various participating healthcare organizations including academic medical centers, specialty physician practices, and community hospitals.The research network encompasses data from nearly 111 million patients.The data remains anonymized and is presented in aggregated form, however the network's integrated analytics capabilities allow for the generation of patient-level data for tasks such as cohort selection and matching, as well as the analysis of the incidence and prevalence of events within a cohort.It also facilitates comparisons of characteristics and outcomes between matched cohorts.For further details about the database, additional information can be accessed online 13 .

Study Population and Design
The TriNetX research network was searched, and data curation was performed on August 31, 2023.A comparative retrospective cohort study was conducted, which included patients ≥ 18 years with preexisting T2DM and a history of prostate cancer who received HT, which included GnRH analogs (leuprolide, triptorelin, goserelin, histrelin, relugolix, degarelix, abarelix) and/or androgen signaling inhibitors (enzalutamide, apalutamide, darolutamide, bicalutamide, unamide, nilutamide and abiraterone) between August 1st, 2013 and August 31st, 2021.We elected to start our search from 2013 since earlier that year that the rst SGLT2i was approved by FDA for the treatment of T2DM (canagli ozin, 3/29/2013) 14,15 .We ended our search in 2021 to allow for two years of follow up.A two-year follow-up period was decided based on the follow-up period used in the previously published SGLT2i trials evaluating cardiovascular outcomes 11,12 .Patients included in this study were further categorized in two cohorts based on their use of SGLT2i (canagli ozin, dapagli ozin, empagli ozin).Various cardiovascular outcomes were obtained during the two years follow-up following the index event de ned as initiation of HT for prostate cancer.
Patients with history of T2DM as well as prostate cancer were identi ed using two de nitions based on the International Classi cation of Diseases, Tenth Revision (ICD-10) code.Identi cation of patients who were prescribed HT as well as SGLT2i was completed using the National Library of Medicine RxNorm terminology.Cohorts were matched using propensity score matching (PSM) using multiple baseline characteristics as deemed clinically signi cant.The Supplementary Appendix provides additional information on cohort de nition criteria, analysis setup, outcome de nitions and PSM.

Main Composite Outcome
The main composite outcome was all-cause mortality, HF, acute MI and peripheral artery disease (PAD) over two years from the index event of HT initiation.HF is any new diagnosis of HF and PAD any type of PAD as de ned by the ICD codes provided in the supplementary appendix.

Secondary Outcomes
Secondary outcomes included individual outcomes of all-cause mortality, new onset HF, acute MI, PAD, HF exacerbation, LVEF < 50%, atrial brillation/ utter, cardiac arrest, ischemic stroke, need for renal replacement therapy and all-cause ER visits/hospitalizations.The outcomes were de ned based on ICD or CPT codes and EHR extracted data.HF exacerbation was de ned by the diagnostic codes plus need for IV diuretics.

Statistical Analysis
Patients with history of T2DM and prostate cancer who received HT were divided into 2 cohorts based on the use of SGLT2i: SGLT2i cohort and non-SGLT2i cohort.These two cohorts were compared using independent sample t-tests for continuous variables, reported as mean (range).Categorical variables are reported as counts (%) and compared using the Chi-square (χ2) test.To control for baseline differences in the patient cohorts, we performed 1:1 Propensity Score matching (PSM) for characteristics of clinical relevance utilizing a built-in algorithm that uses the greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard mean difference (SMD).Any characteristic with a SMD between the cohorts lower than 0.1 was considered well-matched.After propensity matching, time to event analysis reported as hazard ratios with 95% con dence intervals was performed for the primary outcome and odds ratios with 95% con dence intervals for the secondary outcomes using the χ2 for the measures of association.Absolute risk difference (ARD) was calculated as the subtraction of the absolute risk of the event in the treatment (SGLT2i) cohort and the absolute risk of the event in the control (non-SGLT2i) cohort.Furthermore, a sensitivity analysis was performed to evaluate the potential of signi cant confounding.For the sensitivity analysis we calculated Evalues for the odds ratio as previously described 16 .A large E-value means that signi cant unmeasured confounding would be needed to explain away an effect estimate while a small E-value means that little unmeasured confounding would be needed to explain away an effect estimate.Statistical analyses were completed using the TriNetX online platform using R for statistical computing.

Role of Funding Source:
No Funding Source is involved.

Study Population
A total of 26,848 patients were identi ed with a history of T2DM and prostate cancer who received HT.Of the total patients, 2,741 patients received SGLT2i while 24,107 patients did not receive SGLT2i.After propensity score matching, 2,155 patients remained in each cohort (Table 1).

Patient Demographics
Table 1 outlines the baseline characteristics of each cohort before and after propensity matching.The mean age (± SD) of patients in the SGLT2i cohort was 66.8 ± 12.8 and 57.8% of patients were White adults.Before propensity matching, patients treated with SGLT2i had a higher prevalence of comorbidities, including hypertension, hyperlipidemia, ischemic heart disease, cardiomyopathy, HF, atrial brillation/ utter, chronic lower respiratory diseases, and chronic kidney disease.The proportion of metformin, glucagon-like peptide-1 (GLP-1) agonists, as well as insulin use was higher in the SGLT2i cohort.All baseline characteristics between the two cohorts, including healthcare utilization, were propensity matched, with no residual difference (standard mean difference for all included covariates was < 0•1; Table 1).

Main Composite Outcome:
Among patients with a history of T2DM and prostate cancer who received HT, patients who received SGLT2i had a lower risk of developing the composite outcome of all-cause mortality, HF, acute MI and peripheral artery disease over two years since initiation of HT, compared to propensity-matched controls who did not receive SGLT2i (HR 0.689, 95% CI 0.582-0.816;p < 0.001; Table 2; Fig. 1).The composite outcome occurred in 218 patients (16.1%) in the SGLT2i cohort as compared to 355 patients (26.3%) in the non-SGLT2i cohort The E value of the Odds ratio for the primary outcome was 2.47 and the E value for the lower con dence interval was 2.88, both of which support stronger association of SGLT2i with the observed differences in outcomes (Table 2).
Sensitivity analysis with E-values suggests stronger association of SGLT2i on observed outcomes and a low likelihood that differences in the outcomes are due to unmeasured confounders (Table 2).

Discussion
To our knowledge, this is the rst, large, real-world study evaluating the incidence of adverse cardiovascular and renal outcomes among patients with prostate cancer on HT treated with SGLTi compared to other agents for T2DM.We found that among patients with prostate cancer, SGLT2i treatment was associated with a signi cantly lower risk of developing the composite outcome of all-cause mortality, new onset HF, acute MI and PAD over two years since initiation of HT.In the analysis of individual outcomes, SGLT2i were associated with lower odds of new onset HF, HF exacerbation, PAD, atrial brillation/ utter, cardiac arrest, need for RRT, overall ER visits/hospitalizations and all-cause mortality.
Patients with prostate cancer represent a unique patient population with a high burden of comorbid cardiovascular conditions, including T2DM, as well as cardiovascular disease, which is a leading cause of death [2][3][4] .The high prevalence of cardiovascular disease among patients with prostate cancer has been attributed not only to the coexistence of shared risk factors but also the effects of HT.HT is the backbone of prostate cancer therapy and it is used for as many as 50% of patients with prostate cancer at some point in their disease course.In 2006, Keating et al. were one of the rst to report an association between GnRH agonists and increased incidence of DM, coronary heart disease, MI, and sudden cardiac death 6 .Since then, several studies and clinical trials have con rmed that GnRH agonists, abiraterone, androgen receptor antagonists, and less so GnRH antagonists, are associated with increased incidence of adverse cardiovascular events.The mechanism of HT related cardiotoxicity includes hypogonadism-mediated alterations in body composition, with increase in adiposity and decrease in lean mass, lipid abnormalities (increase in triglycerides and LDL cholesterol) and impaired glucose control with decreased insulin sensitivity and subsequently elevated fasting serum glucose 5 .These metabolic derangements lead to an increase in circulating proin ammatory adipokines and prothrombotic markers with subsequent vascular endothelial dysfunction, vascular in ammation, and adverse cardiovascular and renal events 5 .
Over the last decade, several large clinical trials have shown that treatment with SGLT2 inhibitors is associated with favorable cardiovascular and renal outcomes in patients with T2DM at risk of or with established cardiovascular disease but also in patients with HF and chronic kidney disease (CKD) without T2DM [9][10][11][12] .Empagli ozin was the rst SGLT2i that received FDA approval in December of 2016 for reduction of cardiovascular death in adults with T2DM 17 .Subsequently, in May of 2020 FDA approved dapagli ozin for reducing the risk of cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction regardless of diabetes status, 18 and in April of 2021 dapagli ozin was approved to reduce the risk of kidney function decline in adults with CKD 19 .More recently, in February of 2022, FDA approved empagli ozin to reduce the risk of cardiovascular death and hospitalizations in adults with HF regardless of ejection fraction 20 .In addition to the above bene ts, recent evidence suggests that SGLT2i may also reduce the incidence of atrial brillation/ utter 21 .Our study ndings further emphasize the importance of using SGLT2i in patients with T2DM to prevent adverse cardiorenal outcomes.
Considering that cardiovascular disease is a major cause of death among a large portion of men with prostate cancer, treatment with SGLT2i might have a great impact in improving mortality and morbidity.Furthermore, SGLT2i might be able to mitigate the risk of cardiotoxicity mediated by HT.Despite the signi cant potential bene ts, patients with prostate cancer were excluded from the above-mentioned clinical trials and the exact role and size of impact of SGLT2i in preventing adverse cardiovascular and renal outcomes among patients with T2DM and prostate cancer treated with HT has not been examined.Our study is the rst one to report a signi cant reduction in the risk of adverse cardiorenal outcomes among patients with prostate cancer on HT and T2DM treated with vs without SGLT2i.We hypothesize that by inducing glucosuria and natriuresis, SGLT2i improve hyperglycemia and hypertension, the two major risk factors contributing to the development of cardiovascular disease among patients with prostate cancer treated with HT 22,23 .Furthermore, similar to patients with HF, it is likely that SGLT2i alter adipokine signaling and reduce in ammation, which could prevent HT-related cardiotoxicity 22,23 .Based upon clinical observations and convergent data, our group has also postulated that a subset of prostate cancers is part of an "overlap syndrome" of age-related illnesses, including cardiovascular disease, with shared biology 24 .The ndings of this study suggest that SGLT2i warrant further investigation in this subset of patients since it has the potential to improve survival.
In addition to the favorable cardiorenal bene ts of SGLT2i among patients with prostate cancer, preclinical studies have suggested functional expression of SGLT receptors in prostate adenocarcinomas and that treatment with SGLT2i might lead to favorable oncologic outcomes as well 25 .Studies evaluating the role of SGLT2i in prostate cancer-speci c outcomes in human subjects are currently underway (NCT04887935).Such trials may also be able to assess the cardiovascular bene ts of SGLT2i in patients with prostate cancer irrespective of the presence of T2DM.

Study Limitations:
Our study has several limitations including those inherent to observational studies such as selection bias.Most importantly, despite our efforts to carefully control for baseline differences in the SGLT2i versus non-SGLT2i cohort using propensity matching, unmeasured confounding may still exist.To eliminate this possibility, we performed a sensitivity analysis of patients with prostate cancer treated with vs without SGLT2i, the results of which indicated that the ndings are unlikely to be explained by unmeasured confounders.Patients on SGLT2i may have also have socioeconomic differences related to access to medications, which cannot be assessed in this study.Differences in the type of HT that the two patient groups received, and the stage of their prostate cancer could not be assessed either, due to limitations of the database used.Furthermore, retrospective data curated from electronic medical records may be inaccurate or carry the risk of biases.This risk is somewhat mitigated by the large number of patients included in our study and the large effect size.Finally, this study did not assess side effects related to SGLT2i or prostate cancer speci c outcomes.

Conclusions
This study demonstrated that the use of SGLT2i for the treatment of T2DM was associated with signi cantly lower risk for developing the composite outcome of all-cause mortality, new onset HF, acute MI and PAD among patients with prostate cancer treated with HT.Clinical trials assessing the impact of SGLT2i in patients without T2DM or HF in reducing CV events associated with HT or prostate cancer outcomes are needed.

Declarations
Author Declarations: Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Table 1 .
Baseline demographics and clinical characteristics of patients with prostate cancer on androgen deprivation therapy separated by treatment with or without SGLT2 inhibitors for type II diabetes mellitus, before and after propensity score matching.

Table 2 .
Comparison of primary and secondary outcomes of patients with prostate cancer on androgen deprivation therapy who were treated with or without SGLT2 inhibitors for type II diabetes mellitus.Sodium-glucose transport protein 2; ARD Absolute risk difference; HF -heart failure; AMI -acute myocardial infarction; PAD -peripheral artery disease; ER -emergency room FiguresFigure1